2025
LZTR1 is a melanoma oncogene that promotes invasion and suppresses apoptosis
Bacchiocchi A, Mak M, Khan Z, Gong X, Sznol M, Na Z, Su H, Chan L, Yan Q, Zhao D, Mortlock R, Knight J, Slavoff S, Halaban R. LZTR1 is a melanoma oncogene that promotes invasion and suppresses apoptosis. Oncogene 2025, 1-11. PMID: 40885854, DOI: 10.1038/s41388-025-03538-2.Peer-Reviewed Original ResearchDegradation of ubiquitinated proteinsActin-related proteinsActin cytoskeleton organizationUbiquitin-proteasome systemSrc tyrosine kinaseAnchorage-independent growthNormal cell survivalCargo adapterActin organizationProximity biotinylationCytoskeleton organizationLC-MS/MS proteomicsLeucine zipperProteasome systemUbiquitinated proteinsCo-ImmunoprecipitationTargeting Pyk2Cell spreadingMelanoma cellsEnvironmental stressGrowth advantageMolecular characterizationCell migrationCell survivalLZTR1The ERVK3‑1 Microprotein Interacts with the HUSH Complex
Jayatissa A, Jaunbocus N, Erkalo B, Jiang K, Zheng S, Su H, Yan L, Choi J, Vaughan J, Bacchiocchi A, Na Z, Cao X, Halaban R, Saghatelian A, Craft J, Chen Y, Slavoff S. The ERVK3‑1 Microprotein Interacts with the HUSH Complex. Biochemistry 2025, 64: 3372-3381. PMID: 40699144, PMCID: PMC12339190, DOI: 10.1021/acs.biochem.5c00023.Peer-Reviewed Original ResearchConceptsHUSH complexTranscriptional repressionHuman endogenous retrovirusesIntron-less geneRegulation of target gene expressionEndogenous retrovirusesTarget gene expressionGenomic elementsHuman genomeTarget genesGene expressionHuman cellsMicroproteinsExogenous retrovirusesLociGenesRetrovirusesRetrotransposonsGenomeMolecular remnantsRepressionPPHLN1ComplexRegulationBlocking Nitrosylation Induces Immunogenic Cell Death by Sensitizing NRAS-Mutant Melanoma to MEK Inhibitors
Srivastava J, Yadav V, Jimenez R, Phadatare P, Inamdar N, Young M, Bacchiocchi A, Halaban R, Fang B, de Mingo Pulido A, Tsai K, Smalley K, Koomen J, Rodriguez P, Premi S. Blocking Nitrosylation Induces Immunogenic Cell Death by Sensitizing NRAS-Mutant Melanoma to MEK Inhibitors. Cancer Research 2025, 85: 2268-2287. PMID: 40287947, PMCID: PMC12167936, DOI: 10.1158/0008-5472.can-24-0693.Peer-Reviewed Original ResearchConceptsInduce immunogenic cell deathNRAS-mutant melanomaDamage-associated molecular patternsImmunogenic cell deathMEK inhibitorsDendritic cellsRepertoire of CD8+ T cellsCocultures of dendritic cellsCD8+ T cellsCell deathActivating NRAS mutationsAntimelanoma immune responsesImmunocompetent mouse modelInnovative treatment strategiesMEK-ERK signalingAntitumor immunityNRAS mutationsMelanoma subtypesERK MAPK pathwayTargeted therapyTumor microenvironmentT cellsT lymphocytesMelanoma growthTherapeutic resistanceFAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma
Lubrano S, Cervantes-Villagrana R, Faraji F, Ramirez S, Sato K, Adame-Garcia S, Officer A, Arang N, Rigiracciolo D, Anguiano Quiroz P, Martini C, Wang Y, Ferguson F, Bacchiocchi A, Halaban R, Coma S, Holmen S, Pachter J, Aplin A, Gutkind J. FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma. Cancer Cell 2025, 43: 428-445.e6. PMID: 40020669, PMCID: PMC11903146, DOI: 10.1016/j.ccell.2025.02.001.Peer-Reviewed Original ResearchConceptsBRAF V600E melanomaFocal adhesion kinaseV600E melanomaFAK inhibitorActivated focal adhesion kinaseFocal adhesion kinase inhibitionRaf-MEKActivation of focal adhesion signalingFocal adhesion kinase inhibitorResistance to BRAFiSyngeneic mouse modelMAPK pathway inhibitionFocal adhesion signalingPro-apoptotic activityMelanoma patientsAdhesion signalingImmune therapyBRAF mutationsBRAFiTranscriptome analysisMelanomaMouse modelPathway inhibitionBRAFMelanoma cells
2024
Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma
Lu B, Lucca L, Lewis W, Wang J, Nogueira C, Heer S, Rayon-Estrada V, Axisa P, Reeves S, Buitrago-Pocasangre N, Pham G, Kojima M, Wei W, Aizenbud L, Bacchiocchi A, Zhang L, Walewski J, Chiang V, Olino K, Clune J, Halaban R, Kluger Y, Coyle A, Kisielow J, Obermair F, Kluger H, Hafler D. Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma. Nature Immunology 2024, 26: 82-91. PMID: 39609626, PMCID: PMC12285569, DOI: 10.1038/s41590-024-02023-4.Peer-Reviewed Original ResearchCD8+ T cellsAnti-tumor immunityRegulatory T cellsT cellsSubpopulation of CD8+ T cellsCytotoxic CD8+ T cellsHuman CD8+ T cellsTumor antigen-specific CD8Impaired anti-tumor immunityTumor antigen-specificPoor overall survivalTumor rejectionKIR expressionOverall survivalTumor antigensImmune evasionCellular mediatorsHuman cancersCD8MelanomaTumorTranscriptional programsFunctional heterogeneityImmunityPatientsUltra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction
Li X, Liu T, Bacchiocchi A, Li M, Cheng W, Wittkop T, Mendez F, Wang Y, Tang P, Yao Q, Bosenberg M, Sznol M, Yan Q, Faham M, Weng L, Halaban R, Jin H, Hu Z. Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction. EMBO Molecular Medicine 2024, 16: 2188-2209. PMID: 39164471, PMCID: PMC11393307, DOI: 10.1038/s44321-024-00115-0.Peer-Reviewed Original ResearchMolecular residual diseaseCirculating tumor DNAWhole-genome sequencingCell-free DNAGenome sequenceDetection of molecular residual diseaseCirculating tumor DNA detectionResidual disease detectionConsistent with clinical outcomesVariant allele frequencyResidual diseaseMelanoma patientsMonitoring immunotherapyTumor DNAEsophageal cancerClinical outcomesColorectal cancerWGS technologiesAllele frequenciesCancerDNAAnalytical sensitivitySequenceImmunotherapyRelapsePrognostic and therapeutic insights into MIF, DDT, and CD74 in melanoma
Valdez C, Sánchez-Zuno G, Osmani L, Ibrahim W, Galan A, Bacchiocchi A, Halaban R, Kulkarni R, Kang I, Bucala R, Tran T. Prognostic and therapeutic insights into MIF, DDT, and CD74 in melanoma. Oncotarget 2024, 15: 507-520. PMID: 39028303, PMCID: PMC11259151, DOI: 10.18632/oncotarget.28615.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntigens, Differentiation, B-LymphocyteBiomarkers, TumorFemaleHistocompatibility Antigens Class IIHumansImmune Checkpoint InhibitorsIntramolecular OxidoreductasesMacrophage Migration-Inhibitory FactorsMaleMelanomaMiddle AgedMutationPrognosisRetrospective StudiesSkin NeoplasmsConceptsMacrophage migration inhibitory factorImmune checkpoint inhibitionD-dopachrome tautomeraseExpression of macrophage migration inhibitory factorDrivers of tumor progressionInflammatory cell markersPatient tumor samplesPatient survival outcomesMigration inhibitory factorStatistically significant differenceCheckpoint inhibitionImmune therapyPrognostic valueSurvival outcomesResistant melanomaGene expressionImproved survivalRetrospective studyInflammatory markersTumor progressionCell markersTumor samplesClinical evidenceMelanomaBulk RNA sequencingA plasma-based proteomic platform for predicting clinical benefit from immune checkpoint inhibitors in multiple cancers.
Sela I, Lahav C, Lowenthal G, Harel M, Elon Y, Yellin B, Dicker A, Halaban R, Marte J, Sznol M, Gulley J. A plasma-based proteomic platform for predicting clinical benefit from immune checkpoint inhibitors in multiple cancers. Journal Of Clinical Oncology 2024, 42: 2568-2568. DOI: 10.1200/jco.2024.42.16_suppl.2568.Peer-Reviewed Original ResearchNon-small cell lung cancerHPV-related cancersProgression-free survivalPre-treatment plasma samplesInhibitor-based therapySquamous cell carcinomaPD-(L)1Overall survivalCell carcinomaCancer typesClinical benefitImmune checkpoint inhibitor (ICI)-based therapyMetastatic non-small cell lung cancerHead and neck squamous cell carcinomaAnogenital squamous cell carcinomasHazard ratioPD-1 inhibitor monotherapyNeck squamous cell carcinomaMultivariate Cox proportional hazards modelPredicting clinical benefitImmune checkpoint inhibitorsECOG performance statusInhibitor combination therapyPlasma samplesKaplan-Meier methodDigital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma
Su D, Schoenfeld D, Ibrahim W, Cabrejo R, Djureinovic D, Baumann R, Rimm D, Khan S, Halaban R, Kluger H, Olino K, Galan A, Clune J. Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma. Journal For ImmunoTherapy Of Cancer 2024, 12: e008646. PMID: 38519058, PMCID: PMC10961546, DOI: 10.1136/jitc-2023-008646.Peer-Reviewed Original ResearchConceptsCTLA-4 expression levelsCancer-associated fibroblastsAssociated with worse survivalExpression of immune checkpointsLAG-3 expressionDesmoplastic melanomaLymphoid aggregatesCTLA-4PD-1Immune checkpointsIntratumoral leukocytesLAG-3Tumor compartmentsWorse survivalCD20+B cellsIncreased expression of immune checkpointsProgrammed cell death protein 1Macrophage/monocyte markerSentinel lymph node positivityCell death protein 1Associated with poor prognosisLymph node positivityDense fibrous stromaPotential prognostic significanceCore of tumorsInterferon-stimulated neutrophils as a predictor of immunotherapy response
Benguigui M, Cooper T, Kalkar P, Schif-Zuck S, Halaban R, Bacchiocchi A, Kamer I, Deo A, Manobla B, Menachem R, Haj-Shomaly J, Vorontsova A, Raviv Z, Buxbaum C, Christopoulos P, Bar J, Lotem M, Sznol M, Ariel A, Shen-Orr S, Shaked Y. Interferon-stimulated neutrophils as a predictor of immunotherapy response. Cancer Cell 2024, 42: 253-265.e12. PMID: 38181798, PMCID: PMC10864002, DOI: 10.1016/j.ccell.2023.12.005.Peer-Reviewed Original ResearchImmunotherapy responseNon-small cell lung cancerAnti-PD1 responseAnti-PD1 therapyCohort of patientsNon-responsive tumorsCell lung cancerAnti-cancer immunotherapyPre-clinical findingsBlood-borne biomarkersCytotoxic TLung cancerPredictive biomarkersCurrent biomarkersTreatment responseNeutrophilsLY6EBiomarkersActive biomarkersPatientsMiceFurther mechanistic understandingActivationResponseImmunotherapy
2023
Unannotated microprotein EMBOW regulates the interactome and chromatin and mitotic functions of WDR5
Chen Y, Su H, Zhao J, Na Z, Jiang K, Bacchiocchi A, Loh K, Halaban R, Wang Z, Cao X, Slavoff S. Unannotated microprotein EMBOW regulates the interactome and chromatin and mitotic functions of WDR5. Cell Reports 2023, 42: 113145. PMID: 37725512, PMCID: PMC10629662, DOI: 10.1016/j.celrep.2023.113145.Peer-Reviewed Original ResearchConceptsG2/M phaseWD40-repeat protein WDR5Mitotic spindle lengthMultiple interaction partnersM phaseOff-target genesLate G1 phaseWDR5 interactionMitotic functionsH3K4me3 levelsWDR5Interaction partnersMultiple proteinsExpression maximaCell cycleSpindle lengthG1 phaseGenesCell proliferationOff-target bindingBindingInteractomeChromatinTranscriptionKIF2A.CD4 T cells and toxicity from immune checkpoint blockade
Earland N, Zhang W, Usmani A, Nene A, Bacchiocchi A, Chen D, Sznol M, Halaban R, Chaudhuri A, Newman A. CD4 T cells and toxicity from immune checkpoint blockade. Immunological Reviews 2023, 318: 96-109. PMID: 37491734, PMCID: PMC10838135, DOI: 10.1111/imr.13248.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsIrAE developmentHigh-dose corticosteroid treatmentT-cell receptor sequencingT cell abundanceImmune checkpoint blockadeCD4 T cellsICI discontinuationCheckpoint inhibitorsCorticosteroid treatmentAdverse eventsCheckpoint blockadeAdvanced melanomaHospital admissionTreatment initiationRNA sequencingSafety profileCancer patientsTCR diversityT cellsBulk RNA sequencingSingle-cell RNA sequencingOrgan systemsPatientsBaseline featuresA subset of neutrophils as a predictive biomarker for immunotherapy response in patients with non–small-cell lung cancer and melanoma.
Shaked Y, Benguigui M, Halaban R, Bacchiocchi A, Kamer I, Bar J, Lotem M, Shen-Orr S, Sznol M, Cooper T. A subset of neutrophils as a predictive biomarker for immunotherapy response in patients with non–small-cell lung cancer and melanoma. Journal Of Clinical Oncology 2023, 41: 2557-2557. DOI: 10.1200/jco.2023.41.16_suppl.2557.Peer-Reviewed Original ResearchPeripheral blood mononuclear cellsCell lung cancerImmunotherapy outcomesImmunotherapy responseMelanoma patientsCancer patientsLung cancerT cellsImmune checkpoint inhibitor-based therapyNew biomarkersNon-small cell lung cancerAdvanced metastatic NSCLCAnti-PD1 responseImmunotherapy-treated patientsMyeloid cell compositionPDL-1 expressionSubset of neutrophilsAnti-PD1 therapyMalignant melanoma patientsBlood mononuclear cellsInhibitor-based therapyPre-clinical modelsRenal cell carcinomaBlood-borne biomarkersSuccessful clinical trialsDynamic changes of circulating soluble PD-1/PD-L1 and its association with patient survival in immune checkpoint blockade-treated melanoma
Lu L, Risch E, Halaban R, Zhen P, Bacchiocchi A, Risch H. Dynamic changes of circulating soluble PD-1/PD-L1 and its association with patient survival in immune checkpoint blockade-treated melanoma. International Immunopharmacology 2023, 118: 110092. PMID: 37004344, DOI: 10.1016/j.intimp.2023.110092.Peer-Reviewed Original ResearchConceptsImmune checkpoint blockadeSoluble PD-L1 (sPD-L1) levelsPD-L1 ratioPD-L1 levelsSoluble PD-1Soluble PD-L1PD-L1PD-1Patient survivalSurvival statusPD-1/PD-L1Immune checkpoints PD-1T cell exhaustionPatients' survival statusSolid tumor typesInitial immunotherapyCheckpoint blockadeMelanoma patientsPoor prognosisRetrospective studyPatient responseCell exhaustionTumor typesMelanomaSurvival
2022
Author Correction: Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis
Farshidfar F, Rhrissorrakrai K, Levovitz C, Peng C, Knight J, Bacchiocchi A, Su J, Yin M, Sznol M, Ariyan S, Clune J, Olino K, Parida L, Nikolaus J, Zhang M, Zhao S, Wang Y, Huang G, Wan M, Li X, Cao J, Yan Q, Chen X, Newman AM, Halaban R. Author Correction: Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis. Nature Communications 2022, 13: 2704. PMID: 35538087, PMCID: PMC9090916, DOI: 10.1038/s41467-022-30446-w.Peer-Reviewed Original ResearchIntegrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis
Farshidfar F, Rhrissorrakrai K, Levovitz C, Peng C, Knight J, Bacchiocchi A, Su J, Yin M, Sznol M, Ariyan S, Clune J, Olino K, Parida L, Nikolaus J, Zhang M, Zhao S, Wang Y, Huang G, Wan M, Li X, Cao J, Yan Q, Chen X, Newman AM, Halaban R. Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis. Nature Communications 2022, 13: 898. PMID: 35197475, PMCID: PMC8866401, DOI: 10.1038/s41467-022-28566-4.Peer-Reviewed Original ResearchConceptsAcral melanomaMelanoma subtypesClinical profilingCommon melanoma subtypeImmune checkpoint blockadeCheckpoint blockadeInferior survivalMelanoma cell linesKey molecular driversPoor prognosisTherapeutic targetAnchorage-independent growthImmunomodulatory genesNon-white individualsHotspot mutationsMolecular driversCandidate oncogeneMelanomaApoptotic cell deathLZTR1Focal amplificationTumor promoterCell linesMetastasisTumor suppressorT cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma
Lozano AX, Chaudhuri AA, Nene A, Bacchiocchi A, Earland N, Vesely MD, Usmani A, Turner BE, Steen CB, Luca BA, Badri T, Gulati GS, Vahid MR, Khameneh F, Harris PK, Chen DY, Dhodapkar K, Sznol M, Halaban R, Newman AM. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma. Nature Medicine 2022, 28: 353-362. PMID: 35027754, PMCID: PMC8866214, DOI: 10.1038/s41591-021-01623-z.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsImmune-related adverse eventsT-cell characteristicsIrAE developmentBlood samplesSevere immune-related adverse eventsAnti-PD-1 monotherapyCombination immune checkpoint inhibitorsT-cell receptor sequencingT cell abundanceCell receptor sequencingOrgan system involvementPeripheral blood samplesIrAE onsetCheckpoint inhibitorsAdverse eventsCheckpoint blockadeRNA sequencingTCR clonalityCombination therapyPatient cohortSystem involvementClinical managementTCR diversityImmunological state
2021
Retrospective cell lineage reconstruction in humans by using short tandem repeats
Tao L, Raz O, Marx Z, Ghosh MS, Huber S, Greindl-Junghans J, Biezuner T, Amir S, Milo L, Adar R, Levy R, Onn A, Chapal-Ilani N, Berman V, Arie A, Rom G, Oron B, Halaban R, Czyz ZT, Werner-Klein M, Klein CA, Shapiro E. Retrospective cell lineage reconstruction in humans by using short tandem repeats. Cell Reports Methods 2021, 1: 100054. PMID: 34341783, PMCID: PMC8313865, DOI: 10.1016/j.crmeth.2021.100054.Peer-Reviewed Original ResearchConceptsLineage reconstructionShort tandem repeatsCell lineagesTandem repeatsCell lineage reconstructionCell lineage analysisSingle cellsLineage tracing methodHuman cell lineagesGenome editingLineage analysisMolecular inversion probesReconstructed lineagesLineagesDU145 cellsSomatic mutationsDiscovery platformCell of originRepeatsHealthy cellsCellsImportant insightsTissue formationOrganismsDevelopmental history
2020
21 Plasma-based proteomic profiling as a tool for predicting response to immunotherapy in melanoma patients
Harel M, Lahav C, Jacob E, Issler E, Bar H, Dicker A, Sharon O, Bacchiocchi A, Halaban R, Sznol M, Shaked Y. 21 Plasma-based proteomic profiling as a tool for predicting response to immunotherapy in melanoma patients. Journal For ImmunoTherapy Of Cancer 2020, 8: a11-a12. DOI: 10.1136/jitc-2020-sitc2020.0021.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsMelanoma patientsClinical outcomesHost responseNon-small cell lung cancerCell lung cancerNon-responder groupPlasma samplesPro-metastatic effectsAnti-tumor activityPredictive biomarker discoveryProteomic profilingPlasma proteomic analysisAnti-cancer therapyICI therapyCheckpoint inhibitorsRECIST criteriaLung cancerTreatment modalitiesMechanisms of resistanceIndependent cohortPatientsTumor progressionPredictive signatureImmunotherapyA proteomic biomarker discovery platform for predicting clinical benefit of immunotherapy in advanced melanoma.
Shaked Y, Harel M, Issler E, Fremder E, Jacob E, Dahan N, Bar H, Halaban R, Sznol M, Sharon O. A proteomic biomarker discovery platform for predicting clinical benefit of immunotherapy in advanced melanoma. Journal Of Clinical Oncology 2020, 38: 10037-10037. DOI: 10.1200/jco.2020.38.15_suppl.10037.Peer-Reviewed Original ResearchClinical benefitAdvanced melanomaMelanoma patientsTreatment modalitiesPD-1/PD-L1 axisAnti-PD-1 monotherapyCheckpoint inhibitor-based immunotherapyRemarkable clinical benefitAdvanced melanoma patientsPD-L1 axisImmune checkpoint inhibitor-based immunotherapyNon-responder groupNovel predictive biomarkerOngoing prospective studyPlasma samplesHost-mediated mechanismsHost-mediated responsesStable diseaseCancer treatment modalitiesClinical responseClinical outcomesEntire cohortProspective studyCombination therapyCTLA-4
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